Hypertension is conventionally known to be a crucial risk factor for many diseases, such as cerebral infarction, myocardial infarction, myocardial ischemia, atherosclerosis, cardiac failure, cerebral stroke, coronary artery diseases, and peripheral vascular diseases.
In light of this, various hypotensive substances have been discovered and used on hypertensive patients. For example, tripeptides, such as Val-Pro-Pro and Ile-Pro-Pro, and casein hydrolysate containing such tripeptides, have been reported to have angiotensin I converting enzyme inhibitory activity (ACEI activity) and exhibit a hypotensive effect (see Patent Publications 1 and 2).
The definition of hypertensive patients is not completely definite, and may vary depending on the environment or apparatus used in measurement. When measured with a recently popularized 24-hour ambulatory blood pressure monitor, individuals with mean systolic blood pressure (SBP)≧130 mmHg and mean diastolic blood pressure (DBP)≧80 mmHg usually fall under the category (see Non-patent Publication 1).
With the spread of the 24-hour ambulatory blood pressure monitors, circadian variation profile of blood pressure has come to be determined by ABPM (ambulatory blood pressure monitoring) and used in categorization and study of risk factors for various diseases (Non-patent Publication 2).
Circadian profile of blood pressure in humans generally tends to be high in daytime and decline through nighttime to early morning. With regard to such blood pressure profile, it is known to categorize individuals with a ≧10% decline in nighttime mean SBP compared with daytime measurements as dippers, and those with a <10% decline as non-dippers (Non-patent Publication 3), but there is currently no definite provision of classification criteria for dippers and non-dippers. At any rate, it has been reported that individuals with non-dipping circadian profile of blood pressure are more likely to develop cerebral infarction, myocardial infarction, myocardial ischemia, atherosclerosis, cardiac failure, cerebral stroke, coronary artery diseases, peripheral vascular disease, and the like in the morning than dippers.
It has also been revealed that such a trend is observed not only in hypertensive patients, but also in healthy individuals with normal 24-hour mean blood pressure.
Various kinds of hypotensive drugs for hypertensive patients are generally known, including those reducing daytime blood pressure, and those reducing the entire circadian blood pressure with long-lasting efficacy. However, little is known about drugs for approximating mean SBP from night to early morning in normotensive non-dippers, who are conventionally considered not to require hypotensive drugs, to the profile of dippers.
Patent Publications
    Patent Publication 1: JP-6-40994-A    Patent Publication 2: JP-3-120225-ANon-Patent Publications    Non-Patent Publication 1: Guidelines for the Management of Hypertension 2009, Chapter 2: Ketsuatsu Sokutei to Rinsho Hyoka (Blood Pressure Measurement and Clinical Evaluation), p 8-17 (2009), The Japanese Society of Hypertension    Non-Patent Publication 2: Japanese Circulation Journal Vol. 64, Suppl. V, (2000), “24-jikan Ketsuatsukei no Shiyou (ABPM) Kijun ni Kansuru Gaidorain (Guidelines for Standard of ABPM)”, p 1207-1237    Non-Patent Publication 3: “The Impact of Lactotripeptides on Blood Pressure Response in Stage 1 and Stage 2 Hypertensives”, The Journal of Clinical Hypertension, Vol. 12, No. 3, p 153-159 (2010)